rs12663916

Positions:

• chr6-64591961-G-A
• chr6-64591961-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142800.2(EYS):​c.3906C>T​(p.His1302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,499,362 control chromosomes in the GnomAD database, including 13,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (928 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12257 hom.)
• Consequence: EYS NM_001142800.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0400

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-64591961-G-A is Benign according to our data. Variant chr6-64591961-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64591961-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.3906C>T	p.His1302=	synonymous_variant	26/43	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.3906C>T	p.His1302=	synonymous_variant	26/44		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.3906C>T	p.His1302=	synonymous_variant	26/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.3906C>T	p.His1302=	synonymous_variant	26/44	1		ENSP00000359655	P2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15357 AN: 151978 Hom.: 931 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0739

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0995

GnomAD3 exomes AF: 0.109 AC: 13505 AN: 124052 Hom.: 826 AF XY: 0.109 AC XY: 7127 AN XY: 65210

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.0900

Gnomad FIN exome AF: 0.0766

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.129 AC: 173779 AN: 1347266 Hom.: 12257 Cov.: 34 AF XY: 0.129 AC XY: 84760 AN XY: 659530

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.0752

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.0984

Gnomad4 FIN exome AF: 0.0786

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.101 AC: 15352 AN: 152096 Hom.: 928 Cov.: 32 AF XY: 0.0993 AC XY: 7383 AN XY: 74362

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0739

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0985

Alfa AF: 0.0718 Hom.: 126

Bravo AF: 0.105

Asia WGS AF: 0.122 AC: 423 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Retinitis pigmentosa 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.76
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12663916; hg19: chr6-65301854;